Highlights from Recent Cancer Literature
Journal: Cancer Research (2010)

Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT. ATM activation by oxidative stress. Science 2010;330:517–21.Ataxia telangiectasia is a childhood disease associated with DNA-repair deficiency, immunodeficiency, ataxia, and predisposition to lymphoma. The gene mutated in this disorder, Ataxia Telangiectasia Mutated (ATM) is a known sensor of DNA damage and an executor of signaling leading to DNA repair. Less is known about the role of ATM in sensing oxidative stress. In a recently reported study, Guo and colleagues separated the ATM response to DNA damage from the response to oxidative stress. They demonstrated that ATM acts as a redox sensor in human cells, and that oxidation of ATM results in a disulfide crosslinked dimer that is critical to conveying the response to oxidative stress. Importantly, the authors generated a Cys2991 mutant allele of ATM that was proficient in sensing DNA damage but not oxidative stress. Their investigation also included mechanistic studies highlighting a role for Cys 2991 in disulfide bond formation. Although they were unable to identify similar mutations in patients with ataxia telangiectasia, the authors readily identified a patient-derived R3047X mutation that had properties reciprocal to those in Cys2991 by virtue of its proficiency in sensing DNA damage and its deficiency in sensing oxidative stress. These data show that ATM plays a role in sensing oxidative stress and further suggest that clinical manifestations of ataxia telangiectasia in patients result from an inability to effectively regulate reactive oxygen species.Indran I, Hande P, Pervais S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res; Published OnlineFirst November 11, 2010; doi:10.1158/0008-5472.CAN-10-1588.Telomerase has emerged as having a much greater role than telomere maintenance and immortalization. Indran and colleagues report that hTERT expression can be detected in the mitochondria. Moreover, hTERT is shown to play a role in the regulation of basal reactive oxygen species (ROS) levels and endogenous production. Manipulation of hTERT levels in HeLa cells regulated survival through effects on oxidative stress and mitochondrially mediated apoptosis. In particular, hTERT influenced the ability of glutathione to neutralize ROS. Thus, hTERT has a previously unanticipated role in the regulation of ROS production, cellular stress, and thereby apoptosis, indicating that hTERT may modulate sensitivity of tumor cells to anticancer therapies, This possibility is particularly plausible considering that hTERT physically interacts with NF-κB, which, in turn, may regulate expression of a gene that is important for ROS metabolism.Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 2010;18:485–98.Rakhra and colleagues have shown that the ability of oncogene inactivation to elicit oncogene addiction requires an intact immune system. Specifically, they demonstrated that CD4+ T-cells play an important role in regulating the remodeling of the tumor microenvironment that occurs upon inactivation of the MYC oncogene. In the absence of CD4+ T-cells, MYC inactivation failed to induce cellular senescence of tumors and shut down angiogenic pathways. Similarly, BCR-ABL inactivation in leukemia cells also required an intact immune repertoire to induce changes in the microenvironment and tumor regression. To explain their findings, the authors demonstrated that immune cells are required to elicit critical changes in cytokines that occur upon oncogene inactivation, in particular through thrombospondins. These data highlight that oncogene addiction is a non–cell-autonomous process that is dependent upon a complete immune response. These findings imply that the potential activity of new drugs may require analysis in a host with an intact immune system and that manipulation of host immune repertoire may enhance activity of some targeted therapeutics.Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 2010;3:ra81.PI3K and mammalian target of rapamycin (mTOR) represent survival signaling pathways, yet blockade of these signaling pathways in glioma is cytostatic, failing to induce apoptosis in preclinical glioblastoma cells and in xenograft models. To address the question of why blockade of survival signaling fails to promote survival in glioma, Fan and colleagues analyzed the response of therapy-resistant PTEN mutant glioma. Glioma cells induce autophagy as a survival pathway in response to inhibitors of mTORC1, mTORC2, or PI3K/mTOR. In this study, blockade of autophagosome maturation cooperated with inhibition of PI3K/mTOR to induce apoptosis. Surprisingly, however, blockade of autophagosome maturation failed to induce apoptosis in response to inhibition of mTORC1, an observation traced to activation of both Akt and of autophagy as separate survival signals in response to these inhibitors. The PI3K/mTOR inhibitor NVP-BEZ235, now in clinical trials, cooperated with the clinical antimalarial agent chloroquine (which inhibits autophagosome maturation) to induce apoptosis in PTEN mutant glioma xenografts in vivo, suggesting an approach that could be translated for clinical use.Naito S, Bilim V, Yuuki K, Ugolkov A, Motoyama T, Nagaoka A, et al. Glycogen synthase kinase-3 β: a potential prognostic marker and a potential therapeutic target in human bladder cancer. Clin Cancer Res 2010;16:5124–32.In the United States, bladder cancer is the fourth most commonly diagnosed cancer in men and the eighth most common cancer in women. About 70% of the diagnosed cases are superficial noninvasive tumors, a majority of which will progress to invasive cancer. Prediction of which patients will progress from superficial to invasive disease remains a challenge for clinical management of this disease. Glycogen synthase kinase-3β (GSK-3β) is known to be a positive regulator of pancreatic, colon, and kidney cancer cell survival and proliferation. However, its role in bladder cancer remains unknown. In the present study, Naito and colleagues evaluated the expression pattern of GSK-3β in specific cellular compartments of bladder cancer patients by immunohistochemistry and also its correlation with disease progression. They observed aberrant nuclear accumulation of GSK-3β in 62% and 91% of noninvasive and invasive cases, respectively. GSK-3β nuclear staining was significantly associated with high-grade tumors, advanced stage, metastasis, and worse cause-specific survival in bladder cancer patients. Moreover, pharmacologic inhibition or genetic depletion of GSK-3β was found to be associated with decreased viability of bladder cancer cells. A comprehensive screening of bladder cancer patients for GSK-3β expression could be promising for prognostication as well for developing therapeutic strategies.Katakowski M, Buller B, Wang X, Rogers T, Chopp M. Functional microRNA is transferred between glioma cells. Cancer Res 2010;70:8259–63.MicroRNAs (miRNA), a subset of noncoding RNAs, are 17-27-nt long endogenously initiated short RNA molecules that regulate gene expression at the posttranscriptional level and play important roles in many biological functions, including cell differentiation, tumorigenesis, apoptosis and metabolism. Previous studies have shown that specific tumor cells, including gliomas, can secrete microvessels that contain RNAs, including miRNAs. Katakowski and colleagues have investigated whether the miRNAs produced by genetically modified tumors, in this case rat 9L gliosarcoma cells expressing cel-miR-67, could affect adjacent cells containing a luciferase reporter with a complementary sequence to cel-mir-67 resulting in altered luciferase expression. Inhibition of luciferase was in fact observed in adjacent cells, and this suppression was inhibited by the addition of carbenoxolone to cultures, suggesting that this transfer of miRNA might be mediated by gap junction communication. Additionally, in situ hybridization confirmed the presence of cel-mir-67 in cel-mir-67–null 9L cells after co-culture with genetically modified cel-mir-67–expressing cells. This very interesting study confirms the ability of miRNA produced in one cell to be transferred and to be biologically functional—that is, to inhibit targeted protein expression—in an acceptor cell. Although this phenomenon requires further validation in additional tumor models in vitro as well as in vivo, it does suggest that, at least in the context of specific brain tumor cells, miRNA transfer may contribute to regulation of protein levels through a novel mechanism involving transfer of miRNA. This process could play a significant role if it is validated in tumor evolution and progression.